This project studies the role of the endogenous opioid system (EOS) in humans. We have previously completed a dose-response study in normals of high doses of the opiate antagonist, naloxone (up to 4 mg/kg). Significant dose-dependent increases in physiologic (blood pressure and respiratory rate) and hormonal variables (cortisol and growth hormone) were found suggesting progressive EOS blockade with increasing naloxone doses. Normals also experienced dysphoria at high naloxone doses suggesting EOS involvement in the regulation of mood in normals. In a separate double-blind study, high doses of naloxone produced a significant decrease in caloric intake in healthy, normal volunteers supporting hypothesized involvement of the EOS in eating behavior. We have recently added to these data by demonstrating significant naloxone-induced reductions in eating behavior in obese subjects. In previous work, we have studied the relationship between the hypothalamic-pituitary-adrenal axis and the EOS in depressive illness. We have recently observed increased cortisol response to naloxone in both drug-free and medicated schizophrenic patients in comparison to controls. Further work in depressed patients using this paradigm is indicated.